Activating immune receptors consist of multiple single-pass membrane proteins that assemble on the cell surface through specific interactions between their transmembrane domains. These subunits serve separate roles, either as receptor modules that bind extracellular ligands or as signaling modules that are phosphorylated upon receptor-ligand recognition. The majority of the receptor complexes exhibit a common molecular architecture in which two acidic residues from the transmembrane domain of a signaling dimer couple to one basic residue from the transmembrane domain of a receptor subunit through non-covalent protein-protein interactions within the lipid bilayer. These interactions result in what is known as the intramembrane triad. For many of these receptors, a great deal of structural and biochemical information on receptor-ligand interactions is available, but structural details of the membrane-embedded domain, through which the extracellular signal is transmitted to intracellular domains, remain absent. The goal of this research proposal is to obtain a complete view of a trimeric complex formed by the receptor and signaling modules at atomic resolution. More specifically, we will determine by Nuclear Magnetic Resonance Spectroscopy the structure of the intramembrane triad of a natural killer (NK) cell immune receptor, consisting of the transmembrane domains of the dimeric DAP12 signaling module and the NKG2C receptor chain. We will also characterize the structure of another intramembrane triad, formed by the zeta zeta signaling dimer and NKp46 receptor. High resolution structures of the above two triads, which involve two different classes of signaling modules, will represent essentially all known activating immunoreceptors involving the zeta, Fcy, DAP10, and DAP12 signaling subunits. Since the contact points between the receptor module and the signaling module are all within the transmembrane domains, understanding the structural basis of their assembly has profound consequences for how we envision signals to be communicated across the cellular membrane. Knowledge of the mechanism of assembly would allow us to design new immunosuppressants for medical applications.